三阴性乳腺癌（Triple-negative breast cancer，TNBC）因其显著的异质性、高度侵袭性和易复发转移特征，在治疗策略上亟需整合免疫调控与靶向递送技术。近年来，肿瘤免疫治疗通过激活机体免疫系统展现出良好的应用前景，但其疗效仍受到肿瘤免疫抑制微环境及药物递送效率的双重制约。肿瘤相关巨噬细胞（Tumor-associated macrophages，TAMs）在肿瘤微环境中发挥着关键的调控作用。通过将促肿瘤的M2型TAMs重编程为抗肿瘤的M1型，可有效逆转微环境的免疫抑制状态。在此背景下，光热-免疫联合治疗策略凭借其局部热效应不仅可以直接杀伤肿瘤细胞，同时还能增强T细胞浸润，通过协同作用逆转免疫抑制，成为突破单一疗法局限性的重要研究方向。肿瘤靶向精准递送对于提高光热-免疫联合治疗效果至关重要。尽管纳米生物材料凭借其独特的尺寸效应和表面特性在药物负载方面具有优势，但生物屏障的存在仍限制了其肿瘤深部渗透能力。基于细胞衍生材料（如细胞外囊泡和细胞膜）的生物杂化递送系统，通过结合天然趋向性与工程化修饰，显著提升了肿瘤深部穿透能力。此类递送系统可以搭载免疫调节剂、光敏材料等多种功能成分，实现时空可控的靶向递送，为多模态治疗提供了理想的载体支持。

精准递送系统需要根据肿瘤特点进行定制设计。本文首先针对实体瘤术后残留肿瘤和TNBC的病理特征，设计并开发了一系列生物杂化材料，制定了相应的治疗方案，并开展了系统性研究。针对TNBC术后治疗，我们开发了一种杂合膜双驱动精准递送系统，以实现对术后肿瘤的靶向递送和调控，并通过光热-免疫联合治疗抑制肿瘤复发与转移。在实体瘤术后伤口愈合过程中，血小板、中性粒细胞和巨噬细胞会在伤口部位聚集，并诱导出重要的病理生理特征。利用这些病理生理特征，开发针对性递送系统用于术后肿瘤免疫治疗是一项重要策略。该精准递送系统由光敏剂IR820修饰的血小板-中性粒细胞杂合膜包裹R848纳米粒子组成。通过利用肿瘤术后伤口炎性微环境引起的血小板聚集和中性粒细胞趋向的病理特点，双驱动递送系统能够实现R848对术后肿瘤微环境的靶向调控。在荧光成像引导下实现精准递送后，R848能够将M2型TAMs极化为M1，并作为佐剂刺激树突状细胞（Dendritic cells，DCs）成熟，进而激活T细胞免疫。R848的极化作用与CD47阻断共同增强了巨噬细胞对肿瘤细胞的识别和吞噬功能。光热效应通过直接杀伤肿瘤细胞，促进免疫细胞浸润与激活，进一步增强T细胞介导的抗肿瘤免疫反应，最终有效抑制术后肿瘤的复发与转移，并延长了小鼠的生存时间。

针对非手术TNBC的治疗，提升治疗体系对该肿瘤的特异性是必要的设计方向。值得注意的是，TNBC对铁死亡通路具有显著的易感性，而且T细胞对肿瘤细胞铁死亡通路的调节作用可显著提升治疗效果，这为TNBC的精准化联合治疗策略提供了新的思路‌。要实现铁死亡与免疫治疗的有效协同，关键在于高效诱导肿瘤细胞铁死亡、增强特异性免疫反应以及调控肿瘤微环境。铁蛋白是细胞内主要的储铁蛋白，在乳腺癌中过表达，具有提供内源性铁离子的潜力。我们开发了一种针对铁蛋白的无药生物杂化系统，旨在通过光热效应增强肿瘤铁死亡与抗肿瘤免疫的协同治疗效果。该系统由M1型巨噬细胞外囊泡（M1-type macrophage extracellular vesicles，M1EV）和铁蛋白靶向肽HKN₁₅修饰的中空介孔普鲁士蓝（Hollow mesoporous Prussian blue，HMPB）组成。通过利用M1EV的肿瘤归巢特性，该系统能够精确靶向肿瘤部位。M1EV与HMPB共同作用，促进TAMs向M1极化。HMPB进入肿瘤细胞后在HKN₁₅的作用下定位到铁蛋白，通过光热效应激活内源性铁离子，并自身降解补充外源性铁离子，从而显著提高肿瘤细胞的铁含量，打破铁稳态，诱导铁死亡的发生。同时，光热诱导的肿瘤细胞铁死亡也有效促进了DCs的成熟，从而增强T细胞的特异性免疫反应。CD8⁺ T细胞分泌的γ-干扰素进一步刺激肿瘤细胞内脂质的过氧化过程，加速铁死亡的进展，从而形成铁死亡与抗肿瘤免疫协同治疗的正反馈回路。这种利用无药生物杂化系统实现光热增强铁死亡与肿瘤免疫的协同治疗策略，在抑制4T1荷瘤小鼠的肿瘤生长和预防肿瘤转移方面表现出优异的效果。

综上所述，本文针对TNBC的病理特征设计并开发了两种生物杂化材料，用于光热-免疫协同治疗。这两种生物杂化材料整合了纳米材料与细胞衍生材料的特性及优势，利用仿生载体的生物趋向性实现了肿瘤靶向精准递送，从而增强了光热-免疫协同治疗的效果，并有效预防了肿瘤复发与转移。此外，本文初步探索了生物杂化材料介导的肿瘤光热-免疫协同治疗的作用机制，为生物杂化系统的设计、肿瘤靶向递送策略以及多模态治疗方案的优化提供了有价值的范例。

Given its notable heterogeneity, aggressive behavior, and likelihood of recurrence and metastasis, the treatment strategy for triple-negative breast cancer (TNBC) urgently requires the incorporation of immunomodulatory approaches and targeted delivery technologies. Recently, tumor immunotherapy has demonstrated encouraging results by stimulating the immune system; nonetheless, its effectiveness is still hampered by the immunosuppressive nature of the tumor microenvironment and the challenges associated with drug delivery efficiency. Tumor-associated macrophages (TAMs) play a crucial regulatory role within the tumor microenvironment. The strategy of re-educating tumor-promoting M2-type TAMs into anti-tumor M1 phenotypes can effectively reverse the state of tumor immunosuppression. In this context, the combined photothermal-immunotherapy strategy, characterized by its local thermal effect, not only directly kills tumor cells but also enhances T-cell infiltration, thereby reversing immunosuppression through synergistic effects. This approach has emerged as a significant research direction aimed at overcoming the limitations of monotherapy. Tumor-targeted precise delivery is essential for improving the efficacy of combined photothermal-immunotherapy. Despite the advantages of nanomaterials in drug loading due to their unique size effects and surface properties, biological barriers still limit their ability to penetrate deeply into tumors. Biohybrid delivery systems that utilize cell-derived materials, including extracellular vesicles and cell membranes, significantly enhance deep tumor penetration by integrating natural tropism with engineered modifications. These delivery systems can be outfitted with various functional components, such as immunomodulators and photosensitive materials, to facilitate spatiotemporally controlled targeted delivery. This capability provides an ideal vehicle for supporting multimodal therapies.

Precision delivery systems must be custom-designed based on the specific characteristics of tumors. In this paper, we initially designed and developed a range of biohybrid materials, formulated relevant therapeutic protocols, and conducted systematic investigations into the pathological characteristics of postoperative residual tumors and TNBC. To treat postoperative TNBC, we developed a hybrid membrane dual-driven precision delivery system aimed at achieving targeted delivery and modulation of postoperative tumors, thereby inhibiting tumor recurrence and metastasis through a combination of photothermal and immunotherapy. During the postoperative wound healing of solid tumors, an accumulation of platelets, neutrophils, and macrophages occurs at the wound site, inducing significant pathophysiological changes. Exploiting these features to develop targeted delivery systems for postoperative tumor immunotherapy represents a critical strategy. This precision delivery system comprises photosensitizer IR820-modified platelet-neutrophil hybrid membranes loaded with R848 nanoparticles. By utilizing the pathological characteristics of platelet aggregation and the neutrophil tropism induced by the inflammatory microenvironment of postoperative oncological wounds, the dual-drive delivery system enables targeted modulation of the postoperative tumor microenvironment by R848. Following precise delivery, guided by fluorescence imaging, R848 can polarize M2 macrophages into M1 macrophages and act as an adjuvant to stimulate the maturation of dendritic cells (DCs), activating T-cell immunity. The polarizing effect of R848, in conjunction with the blockade of CD47, enhances the recognition and phagocytosis of tumor cells by macrophages. Furthermore, the photothermal effect amplifies the T-cell-mediated anti-tumor immune response by directly killing tumor cells and promoting immune cell infiltration and activation, ultimately leading to effective inhibition of tumor recurrence and metastasis following surgery and prolonging the survival time of mice.

In the treatment of nonoperative TNBC, enhancing the specificity of the treatment system for the tumor represents a crucial design direction. Notably, TNBC exhibits a significant susceptibility to the ferroptosis pathway. Furthermore, the regulatory influence of T cells on the ferroptosis pathway in tumor cells can markedly enhance therapeutic efficacy, thereby offering a novel approach to the precise combination therapy strategy for TNBC. Effective synergy between ferroptosis and immunotherapy requires ‌boosting ferroptosis in tumor cells‌, ‌activating adaptive immunity‌, and ‌reprogramming the tumor microenvironment‌. Ferritin, the principal intracellular iron storage protein, is overexpressed in breast cancer and has the potential to supply endogenous iron ions. We have developed a drug-free biohybrid system targeting ferritin, aiming to amplify the synergistic therapeutic effects of tumor ferroptosis and anti-tumor immunity through photothermal effects. The system comprises M1-type macrophage extracellular vesicles (M1EV) and ferritin-targeting peptide HKN₁₅-modified hollow mesoporous Prussian blue (HMPB) nanoparticles, which leverage the tumor-homing properties of M1EV to target tumor sites accurately. M1EV acts in conjunction with HMPB to promote the repolarization of TAMs towards the M1 phenotype. HMPB enters tumor cells and localizes to ferritin through the action of HKN₁₅, activating endogenous iron ions via the photothermal effect while also providing exogenous iron ions through its degradation. This significantly increases the iron content within tumor cells, disrupts iron homeostasis, and induces the onset of ferroptosis. Concurrently, photothermal-induced ferroptosis in tumor cells effectively promotes the maturation of DCs, thereby enhancing the specific immune response of T cells. Interferon-gamma secreted by CD8⁺ T cells further stimulates the lipid peroxidation process in tumor cells, accelerating the progression of ferroptosis and establishing a positive feedback loop between ferroptosis and anti-tumor immunity. This synergistic therapeutic strategy employs photothermal enhancement of ferroptosis and tumor immunity through a drug-free biohybrid system, demonstrating significant efficacy in inhibiting tumor growth and preventing tumor metastasis in 4T1 tumor-bearing mice.

In summary, this paper designed and developed two biohybrid materials for photothermal-immuno-synergistic therapy targeting the pathological characteristics of TNBC. The biohybrid materials integrate the properties and advantages of nanomaterials and cell-derived materials, achieving precise tumor-targeted delivery through the biological tropism of biomimetic carriers. This approach enhances the efficacy of photothermal-immuno-synergistic treatment and effectively prevents tumor recurrence and metastasis. Furthermore, this paper initially explored the mechanisms underlying biohybrid material-mediated photothermal-immuno-synergistic therapy for tumors, providing valuable insights for the design of biohybrid systems, tumor-targeted delivery strategies, and the optimization of multimodal therapeutic regimens.